Direct functionalization of benzoquinolines

Article abstract of DOI:10.2174/157017810790533986

The first direct lithiation of the pyridine ring of benzo[h]- and benzo[f]- quinolines is reported. The method allowed the introduction of different electrophiles (Cl, Br and SPh) in 2-position. Other groups were introduced by direct nucleophilic addition of alkyllithiums allowing further transformations to functional groups such as esters and thiolesters.

Full text of DOI:10.2174/157017810790533986

90
Letters in Organic Chemistry, 2010, 7, 90-93
Direct Functionalization of Benzoquinolines
Victor Mamane*, Frédéric Louërat and Yves Fort
Laboratoire SRSMC, Equipe Synthèse Organométallique et Réactivité, UMR 7565, CNRS - Nancy Université, BP
70239, 54506 Vandoeuvre-Lès-Nancy, France
Received March 23, 2009: Revised November 23, 2009: Accepted November 24, 2009
Abstract: The first direct lithiation of the pyridine ring of benzo[h]- and benzo[f]- quinolines is reported. The method
allowed the introduction of different electrophiles (Cl, Br and SPh) in 2-position. Other groups were introduced by direct
nucleophilic addition of alkyllithiums allowing further transformations to functional groups such as esters and thiolesters.
Keywords: Benzoquinoline, functionalization, lithiation, addition.
Due to their coordinating properties, functional
benzoquinoline derivatives are recognized for a long time for
their use in photophysical applications [1] as well as in
catalysis [2]. The requirement of an internal chelating group
(CG) is the pre-requisite for obtaining good coordinating
properties. This CG can be installed in two positions for each
benzoquinoline; C-3 or C-5 for benzo[f]quinoline (1)
(structures 1A and 1B respectively) and C-2 or C-10 for
benzo[h]quinoline (2) (structures 2A and 2B respectively)
(Fig. (1)).
C-5 substituted benzo[f]quinolines starting from simple
pyridines [6]. Following our research efforts toward the
synthesis and functionalization of polyheterocyclic
compounds [7], we now wish to report on the direct
functionalization of benzo[f]quinoline (1) at C-2 and
benzo[h]quinoline (2) at C-3. Two complementary methods
were utilized to achieve this goal: i) the direct lithiation of C-
3 and C-2; and ii) an improved procedure to introduce a
methyl group in C-3 and C-2 followed by further
transformation.
CG
5
The lithiation of pyridine and derivatives is known to
proceed in 2-position by using the superbase n-BuLi-
LiDMAE (lithium dimethylaminoethanolate) in apolar
solvents (hexane, toluene) [8]. The reaction was also
successfully applied to the more electrophilic quinoline.
Although nucleophilic addition could not be totally
suppressed in this case (typically 10-20%), C-2-substituted
derivatives were nevertheless obtained in good yields [9].
During our study on the lithiation of benzo[f]quinoline (1),
we observed that this compound was less reactive toward
deprotonation than the parent pyridine and quinoline. Indeed,
excess of the superbasic system n-BuLi-LiDMAE (8 equiv.)
and prolonged reaction times (16h) at -78°C were necessary
to achieve complete conversion [10]. Quenching the reaction
mixture with different electrophiles such as C2Cl6, CBr4 and
PhSSPh generated compounds 3-5 in good yields.
Unexpected product 6 was obtained by using MeSSMe as an
electrophile in moderate yield. We assume that the expected
thiomethyl adduct is highly reactive under excess of base.
The product 6 was then obtained after successive two
metalation/trapping sequences. The reaction conditions were
optimized in case of 2 since complete formation of 2-
lithiobenzo[h]quinoline was observed only after 24h
followed by trapping with C2Cl6 or CBr4 to afford
compounds 7 [6] and 8 [2a] respectively in good yields [11]
(Scheme 1).
N
N
3
CG
1A
1B
2
N
N
10
CG
CG
2A
2B
Fig. (1). Potential positions for chelating group (CG) presence in
benzoquinolines.
Direct methods to selectively functionalize commercial
benzoquinolines at the desired positions are wished in order
to avoid long reaction sequences. In this context, the
nitrogen-directed C-H activation of 2 at C-10 was intensively
described in the literature [3]. Positions close to the nitrogen
atom (C-3 in 1 and C-2 in 2) are known to be electrophilic
thus allowing the direct nucleophilic addition of
alkyllithiums but the yields described were generally low to
moderate [4]. Other methods required the initial oxidation of
the nitrogen atom [5]. In order to circumvent the difficulty to
functionalize 1 at C-5 by direct methods, we have recently
described a two-step sequence that allowed the synthesis of
Our second approach concerned the efficient direct
nucleophilic addition of alkyllithium compounds on 1 and 2.
Our interest in this reaction was driven by our recent finding
that methyl group of picolines and derivatives can be easily
transformed to different functional groups through the
formation of dithioacetals and trithioorthoesters [12]. Test
*Address correspondence to this author at the Laboratoire SRSMC, Equipe
Synthèse Organométallique et Réactivité, UMR 7565, CNRS - Nancy
Université, BP 70239, 54506 Vandoeuvre-Lès-Nancy, France;
E-mail: victor.mamane@srsmc.uhp-nancy.fr
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Direct Functionalization of Benzoquinolines
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
91
desulfurization with mercuric salts. By adjusting the reaction
conditions, esters 17, 19 [2b] and thiolesters 18, 20 were
then obtained in 56-75% yields (Scheme 3) [18].
N
N
11
12
1
2
1) 5 equiv. KDA
THF, -78°C
2) 5 equiv. MeSSMe
-78 to -60°C
1) 8 equiv. n-BuLi-LiDMAE
Toluene, -78°C, 16-24h
2) 10 equiv. Electrophile
THF, -78°C, 1h
3) H2O
3) Hydrolysis
SMe
SMe
SMe
N
N
E
N
N
15 (83%)
16 (67%)
MeS
SMe
SMe
E
Method A: 3.3 equiv HgCl2
1.65 equiv HgO
E = Cl
E = Br
E = SPh
3 (92%)
7 (94%)
8 (93%)
4 (68%)
5 (74%)
MeOH/H2O 4/1
Method B: 2.2 equiv HgCl2
2.2 equiv CaCO3
E = SCH(SMe)2
6 (49%)
CH3CN/H2O 4/1
Scheme 1. Lithiation and electrophilic trapping of benzoquinolines
1 and 2.
N
COR
reactions were carried out with n-BuLi and benzo[f]quinoline
(1). We have found that the combination of 1.2 equiv. of n-
BuLi and DME (dimethoxyethane) was very efficient for the
addition reaction and allowed fast and clean reactions at
room temperature to give 2-butylbenzoquinolines 9 and 10 in
excellent yields (Scheme 2) [13]. The presence of DME
allowed decreasing the amount of n-BuLi with faster
reaction times [14]. The use of MeLi and PhLi with DME
proceeded also very well to give 2-methylbenzoquinolines
11 [15], 12 [4(a)] and 2-phenylbenzoquinolines 13 [4(b)], 14
[16] in good yields. It must be noted that in some cases, the
spontaneous oxidation of the formed heterocycle is slow (24-
48h) and could be accelerated by the addition of two
equivalents of MnO2. The benzoquinoline derivatives were
then obtained in 2-3h of reaction under air atmosphere.
N
COR
R = OMe
(Method A)
17 (56%)
19 (62%)
R = SMe
(Method B)
18 (72%)
20 (75%)
Scheme 3. Synthesis of ester and thiolester benzoquinoline
derivatives.
In summary, benzo[h]- and benzo[f]quinoline have been
functionalized on the pyridine ring by two different ways
thus allowing the introduction of various functional groups.
The direct lithiation was achieved by regrouping the
requisite conditions for aggregates’ formation: n-BuLi-
LiDMAE superbase in an apolar solvent (toluene). In
contrast, the nucleophilic addition was effective when
working in a polar solvent (Et2O) and in the presence of a
lithium coordinating molecule such as DME that diminishes
the aggregates’ formation. Finally, esters and thiolesters
containing-compounds were obtained in satisfactory yields
from methyl-substituted derivatives.
1
2
1) 1.2 equiv. RLi
1.2 equiv. DME,
Et2O, rt, 2h
2) Hydrolysis, air or MnO2
N
R
ACKNOWLEDGEMENTS
N
R
The authors gratefully acknowledge the CNRS and
Nancy University for financial support.
R = Bu
R = Me
R = Ph
9 ( 84%)
11 ( 65%)
13 ( 91%)
10 ( 90%)
12 ( 66%)
14 ( 86%)
REFERENCES AND NOTES
Scheme 2. Synthesis of alkyl- and aryl-benzoquinolines.
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DMDS (5 equiv) gave the trithioorthoesters 15 and 16
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a
rational derivatization of 10-

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[11]
General procedure: n-Butyllithium (2.5M in hexane, 7.15 mL, 17.6
mmol) was added dropwise to
a
solution of 2-
dimethylaminoethanol (0.89 mL, 8.8 mmol) in toluene (10 mL) at -
5 °C. After 30 min of stirring, the mixture was allowed to cool to -
78 °C. A solution of benzoquinoline (200 mg, 1.1 mmol) in toluene
(2 mL) was then added dropwise. The solution was stirred for 16-
24 h at -78°C and then treated at -78 °C with a solution of the
appropriate electrophile (11 mmol) in THF (10 mL). The
temperature was maintained at -78 °C for 1 h and at 0 °C for 30
min. Hydrolysis was then performed at 0°C (3 mL). The organic
phase was separated and washed with water. After drying over
MgSO4 and evaporation of the solvent, the crude product was
purified by column chromatography. 3-Chloro-benzo[f]quinoline
[2]
(3): 1H NMR (CDCl3) ꢀ 8.82 (d, J = 8.5Hz, 1H), 8.51 (d, J =
8.3Hz, 1H), 7.86-8.01 (m, 2H), 7.65-7.70 (m, 2H), 7.51 (d, J =
8.5Hz, 1H); 13C NMR (CDCl3) ꢀ 122.2, 122.6, 124.1, 127.1, 127.6,
127.7, 128.9, 129.2, 131.6, 132.2, 133.7, 148.2, 150.4; MS (EI) m/z
1
214 (100, M+), 178 (65). 3-Bromo-benzo[f]quinoline (4): H NMR
[3]
(CDCl3) ꢀ 8.71 (d, J = 8.3Hz, 1H), 8.51 (d, J = 8.1Hz, 1H), 7.87-
8.00 (m, 3H), 7.62-7.70 (m, 3H); 13C NMR (CDCl3) ꢀ 122.7, 124.4,
125.7, 127.1, 127.6, 127.8, 128.9, 129.3, 131.7, 132.2, 133.3,
141.5, 148.9; MS (EI) m/z 259 (50, M+[79Br]), 257 (50, M+[81Br]),
178 (100), 151 (60). HRMS m/z calcd for C13H8BrN: 256.9840,
found 257.9932 (MH+). 3-Phenylthio-benzo[f]quinoline (5): 1H
NMR (CDCl3) ꢀ 8.67 (d, J = 8.7Hz, 1H), 8.47 (d, J = 8.1Hz, 1H),
7.86-7.98 (m, 3H), 7.59-7.72 (m, 4H), 7.45-7.90 (m, 3H), 7.11 (d, J
= 8.7Hz, 1H); 13C NMR (CDCl3) ꢀ 119.3, 122.3, 122.6, 127.0,
127.3, 127.5, 128.8, 129.4, 129.6, 129.8, 130.4, 130.9, 131.4,
131.5, 133.1, 135.3, 137.7; MS (EI) m/z 286(100, M+), 151 (18). 3-
(Bis-methylthio-methylthio)-benzo[f]quinoline (6): 1H NMR
(CDCl3) ꢀ 8.97 (d, J = 8.2Hz, 1H), 8.62 (d, J = 8.0Hz, 1H), 7.94-
8.00 (m, 3H), 7.60-7.76 (m, 3H), 5.88 (s, 1H), 1.66 (s, 6H); 13C
[4]
[5]
NMR (CDCl3) ꢀ 30.8, 71.8, 117.1, 118.7, 122.7, 124.1, 127.2,
127.3, 127.8, 128.7, 129.5, 131.3, 131.7, 132.2, 145.9. MS (EI) m/z
222 (100, [M-(SCH3)2]), 180 (25), 151 (16).
Mamane, V.; Aubert, E.; Fort, Y. The methyl group as a source of
structural diversity in heterocyclic chemistry: side-chain
functionalization of picolines and related heterocycles. J. Org.
Chem., 2007, 72, 7294.
[12]
[13]
General procedure: To a solution of benzoquinoline (200 mg, 1.1
mmol) and DME (0.12 mL, 1.1 mmol) in ether (10 mL) at room
temperature was added dropwise n-butyllithium (2.5M in hexane,
0.54 mL, 1.32 mmol). After 2h of stirring, water was added and the
organic phase was separated, dried over MgSO4 and evaporated.
When the rearomatization was incomplete (shown by 1H NMR),
the crude product was dissolved in dichloromethane (5 mL) and
treated with MnO2 (191 mg, 2.2 mmol) at room temperature for 2h.
The black mixture was adsorbed on silica gel and purified by
[6]
[7]
1
column chromatography. 3-Butyl-benzo[f]quinoline (9): H NMR
(CDCl3) ꢀ 8.45 (d, J = 8.3Hz, 1H), 8.25 (d, J = 7.6Hz, 1H), 7.92 (d,
J = 8.2Hz, 1H), 7.67-7.79 (m, 2H), 7.41-7.46 (m, 2H), 7.11 (d, J =
8.3Hz, 1H), 2.90 (t, J = 5.5Hz, 2H), 1.74 (q, J = 5.5Hz, 2H), 1.40
(q, J = 5.5Hz, 2H), 0.93 (t, J = 5.5Hz, 3H); 13C NMR (CDCl3) ꢀ
13.8, 22.5, 32.0, 38.4, 120.7, 122.0, 123.0, 126.3, 126.5, 127.7,
128.2, 129.3, 130.2, 130.4, 130.9, 174.4, 162.1; MS (EI) m/z 235
(3, M+), 193(100). 2-Butyl-benzo[h]quinoline (10): 1H NMR
(CDCl3) ꢀ 9.38 (d, J = 7.5Hz, 1H), 7.92 (d, J = 7.9Hz, 1H), 7.82 (d,
J = 7.6Hz, 1H), 7.51-7.68 (m, 4H), 7.26 (d, J = 7.0Hz, 1H), 3.02 (t,
J = 5.5Hz, 2H), 1.87 (q, J = 5.5Hz, 2H), 1.43 (q, J = 5.5Hz, 2H),
0.97 (t, J = 5.5Hz, 3H); 13C NMR (CDCl3) d 14.1, 22.6, 31.8, 38.7,
121.5, 124.2, 124.6, 125.2, 126.4, 126.6, 127.6, 127.8, 131.5,
133.6, 135.6, 145.8, 161.5; MS (EI) m/z 235 (7, M+), 193 (100).
(a) Louërat, F.; Fort, Y.; Mamane, V. Direct 1,4-difunctionalization
of isoquinoline. Tetrahedron Lett., 2009, 50, 5716. (b) Alexakis,
A.; Amiot, F. Enantioselective addition of organolithium reagents
on isoquinoline. Tetrahedron Asymmetry, 2002, 13, 2117.
[8]
(a) Gros, P.; Fort, Y. Combinations of alkyllithiums and lithium
aminoalkoxides for generation of functional pyridine
organometallics and derivatives. Eur. J. Org. Chem., 2009, 4199.
(b) Gros, P.; Fort, Y. nBuLi/lithium aminoalkoxide aggregates:
new and promising lithiating agents for pyridine derivatives. Eur. J.
Org. Chem., 2002, 3375. (c) Gros, P.; Fort, Y.; Quéguiner, G.;
Caubère, P. Aggregative activation and heterocyclic chemistry III.
Unusual
regioselective
lithiation
of 2-alkoxy-pyridines.
Tetrahedron Lett., 1995, 36, 4791.
[14]
[15]
[9]
Gros, P.; Fort, Y.; Caubère, P. Aggregative activation in
heterocyclic chemistry. Part 5. Lithiation of pyridine and quinoline
with the complex base BuLi·Me2N(CH2)2OLi (BuLi·LiDMAE). J.
Chem. Soc. Perkin Trans. 1, 1997, 24, 3597.
Excess of n-BuLi-LiDMAE was shown to be necessary with other
substrates, see: (a) Loüerat, F.; Gros, P.; Fort, Y. Metallation versus
heteroatom lithium complexation: mono- and -dilithiation of
Compound 11 is commercially available and can be purchased
from Alfa Aesar.
[10]

Direct Functionalization of Benzoquinolines
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
93
13C NMR (CDCl3) ꢀ 53.2, 121.8, 122.8, 123.2, 127.2, 127.5, 128.3,
128.4, 128.7, 128.8, 131.9, 147.0, 147.1, 165.9; MS (EI) m/z 237
(25, M+), 179 (100), 151 (22). Benzo[f]quinoline-3-carbothioic acid
[16]
Li, A.-H.; Ahmed, E.; Chen, X.; Cox, M.; Crew, A. P.; Dong,
H.-Q.; Jin, M.; Ma, L.; Panicker, B.; Siu, K. W.; Steinig, A. G.;
Stolz, K. M.; Tavares, P. A. R.; Volk, B.; Weng, Q.; Werner, D.;
Mulvihill, M. J. A highly effective one-pot synthesis of quinolines
from o-nitroarylcarbaldehydes. Org. Biomol. Chem., 2007, 5, 61.
3-(Tris-methylthio-methyl)benzo[f]quinoline (15): 1H NMR
(CDCl3) ꢀ 8.92 (d, J = 8.8Hz, 1H), 8.57 (d, J = 7.6Hz, 1H), 8.32 (d,
J = 8.8Hz, 1H), 7.99 (2d, J = 8.8Hz, 2H), 7.90 (d, J = 8.2 Hz, 1H),
7.63 (m, 2H), 1.99 (s, 9H); 13C NMR (CDCl3) ꢀ 13.3, 77.2, 112.7,
120.5, 122.5, 123.9, 126.7, 126.9, 127.1, 128.0, 128.5, 129.1,
130.5, 131.5, 131.7, 145.4, 159.9; MS (EI) m/z 284 (100, [M-
SMe]+), 236 (55), 178 (23). Compound 16 was contaminated with a
1
S-methyl ester (18): H NMR (CDCl3) ꢀ 8.94 (d, J = 8.4 Hz, 1H),
8.53 (dd, J = 5.2, 3.2 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.01 (d, J =
9.2, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.89 (m, 1H), 7.65 (dd, J = 5.8, 3
Hz, 2H); 13C NMR (CDCl3) ꢀ 11.6, 117.2, 123.1, 127.3, 128.0,
128.2, 128.7, 128.9, 131.7, 132.3, 147.1, 150.8, 194.3; MS (EI) m/z
253 (15, M+), 225 (12), 206 (15), 178 (100), 151 (28). HRMS m/z
calcd for C15H11NOS: 253.0561, found 254.0634 (MH+).
Benzo[h]quinoline-2-carbothioic acid S-methyl ester (20): 1H NMR
(CDCl3) ꢀ 9.28 (d, J = 7.6 Hz, 1H), 8.07 (2d, J = 8.2 Hz, 2H), 7.90-
7.60 (m, 4H), 7.52 (d, J = 8.8 Hz, 1H), 2.49 (s, 9H); 13C NMR
[17]
1
little amount of starting 2: H NMR (CDCl3) ꢀ 9.32 (d, J = 8Hz,
1H), 8.19 (d, J = 8.6Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.80-7.60
(m, 5H), 1.93 (s, 9H).
(CDCl3) ꢀ 11.6, 117.3, 124.6, 124.7, 127.5, 127.7, 128.7, 128.8,
129.9, 131.1, 133.5, 136.6, 145.3, 149.5, 194.7; MS (EI) m/z 253
(20, M+), 206 (18), 178 (100), 151 (25). HRMS m/z calcd for
C15H11NOS: 253.0561, found 254.0634 (MH+).
[18]
Benzo[f]quinoline-3-carboxylic acid methyl ester (17): 1H NMR
(CDCl3) ꢀ 9.08 (d, J = 9 Hz, 1H), 8.65 (dd, J = 8, 1 Hz, 1H), 8.37
(d, J = 8.4 Hz, 1H), 8.20-7.90 (m, 3H), 7.73 (m, 2H), 4.11 (s, 3H);